Patterns of Linkage Disequilibrium in the Human Genome Chris Levasseur BI 820 March 30, 2003

Linkage Disequilibrium (LD) Particular alleles at neighboring loci tend to be co-inherited. For tightly linked loci this can lead to associations between alleles in the population - LD Might facilitate mapping of complex disease loci through whole-genome association studies

LD Around an Ancestral Mutation

Quantifying Linkage Disequilibrium (D) D = PAB - (PA X PB) A,a and A,b: two alleles at two adjacent loci (A and B) PAB: frequency of the haplotype of alleles A and B PA: frequency of A at the first locus PB: frequency of B at the second locus 0 < D < PAB Raw measurement of Disequilibrium

Absolute Value of Disequilibrium (D’) D depends on allele frequencies D’ = (PAB - PA X PB) / (PA X PB) D’ = 1 if, and only if 2 SNPs have not been separated by recombination during history of the sample (complete LD) If D’ < 1 then the complete ancestral LD has been disrupted If D’ = 0 then there is complete linkage equilibrium * D’ normalizes LD to be between 0 and 1

LD Decays Over Time Due to Recombination

Quantifying LD Decay Dt = (1 - r)tD0 t = time r = recombination fraction between markers D0 = extent of disequilibrium @ starting point Dt = extent of disequilibrium t generations later

Factors That Influence LD Collapse Bottleneck Diversity LD

Factors That Influence LD Expansion Diversity LD

Factors That Influence LD Natural selection Positive selection = LD

Conclusions Lots of variability in the extent of LD from one region of genome to another. Even in a region of high LD, some pairs of loci do not show useful levels of LD due to gene conversions, allele frequency, etc. Do not know if patterns of LD in one pop. will be replicated in other pops. w/ differing histories Many forces shape the patterns of LD in humans (both molecular and demographic forces).